工程化益生菌用于肿瘤靶向联合化学免疫治疗
Engineered probiotics for tumor-targeted combination chemoimmunotherapy.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
乙酰辅酶 A 羧化酶阻碍肿瘤微环境中 CD8(+) T 细胞的脂质利用
英文原题：Acetyl-CoA carboxylase obstructs CD8(+) T cell lipid utilization in the tumor microenvironment.
查看英文原题
Acetyl-CoA carboxylase obstructs CD8(+) T cell lipid utilization in the tumor microenvironment.
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中文摘要
实体瘤微环境（TME）使肿瘤浸润T细胞（TILs）处于代谢受损状态，其特征是无法维持有效的能量合成以支持抗肿瘤功能和存活。TME中的T细胞必须通过线粒体脂肪酸氧化（FAO）分解代谢脂质，以在营养应激下供应能量，且已证实富含FAO的T细胞擅长控制肿瘤。然而，内源性TILs和未修饰的细胞治疗产品无法在肿瘤中维持生物能量学。我们发现，实体TME持续施加乙酰辅酶A（CoA）羧化酶（ACC）活性，引发TILs中脂质生物合成和储存，从而对抗FAO。利用代谢、脂质组学和共聚焦成像策略，我们发现限制ACC可重编程T细胞代谢，使其能够在TME应激中维持能量。限制ACC活性可增强指示T细胞长寿的基因和表型程序，使T细胞具有增加的存活率和多功能性，从而维持肿瘤控制。
展开英文摘要原文
The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor-infiltrating T cells (TILs), hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control.
However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors.
We reveal that the solid TME imposes perpetual acetyl-coenzyme A (CoA) carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, which sustains cancer control.
论文信息
- 作者
- Hunt EG、Hurst KE、Riesenberg BP、Kennedy AS、Gandy EJ、Andrews AM、Del Mar Alicea Pauneto C、Ball LE
- 第一作者单位
- Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.United States
- 通讯作者单位
- Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA. Electronic address: jess_thaxton@med.unc.edu.United States
- 文献类型
- 非美国政府资助研究 · 美国 NIH 资助研究
- 期刊
- Cell metabolism2024 May 7
- 原文标识
- PubMed 38490211 · DOI 10.1016/j.cmet.2024.02.009
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